Based on the results of several studies, serotonin-selective reuptake inhibitors (SSRIs) have not shown promise as anti-smoking pharmacotherapies [5, 9]. However, bupropion and several SSRIs (including fluoxetine, sertraline, fluvoxamine and paroxetine) have been shown using in vitro studies to bind, at clinically relevant concentrations, to the non-competitive ion channel site of the high-affinity nAChR [11], the same site to which mecamylamine (MEC) binds. Since MEC has been shown to have mood-enhancing effects in a controlled smoking cessation study examining the combination of MEC and NTP [13], and recently to have mood-stabilizing properties in patients with bipolar symptoms [14], we speculate that the combination of MEC with an SSRI may have significant positive effects on both depressive symptoms and smoking. In on-going work at Yale using transgenic mice with deletion of the alpha 2-subunit of the nAChR, Picciotto and colleagues have demonstrated that the antidepressant effects of the tricyclic antidepressant amitriptyline in a learned helplessness model of depression are abolished in alpha 2-subunit knock-out mice (which lack functional high-affinity nAChRs containing the alpha 2-subunit) compared to the control background (C57B/L) mouse strain (M.R. Picciotto, Ph.D., personal communication). This finding suggests that the presence of functional nAChRs is necessary, but not sufficient, for generation of antidepressant responses to amitriptyline, an antidepressant that has also been shown to non-competitively inhibit high-affinity nAChRs [11]. Thus, since both SSRIs and MEC bind to nAChRs and since nAChRs may mediate the effects of most clinically effective of antidepressants, it is possible that the combination of MEC with an SSRI may serve to augment partial antidepressant responses to SSRIs, and reduce the drive to smoke in these patients, either primarily or secondarily.